Medical uses of in situ formed gels

ABSTRACT

Balanced pH, hyperosmotic, hypoosmotic, or isoosmotic gels are ideal vehicles for drug delivery. They are especially suited for topical body cavity or injection application of drugs or diagnostic agents; for drug or diagnostic agent delivery to the eye of a mammal; as protective corneal shields; or as ablatable corneal masks useful in laser reprofiling of the cornea. The compositions without the addition of a drug or diagnostic agent are useful as medical devices, for instance, in separating surgically or otherwise injured tissue as a means of preventing adhesions.

This is a continuation of Ser. No. 08/174,101, filed Dec. 28, 1993, nowU.S. Pat. No. 5,587,175, which is a continuation of U.S. Ser. No.07/785,305, filed Oct. 30, 1991, now U.S. Pat. No. 5,318,780, each ofwhich are hereby incorporated by reference in their entireties.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to drug delivery system, the prevention ofpost-surgical adhesions, ophthalmic corneal protective devices, and asurgical device used in the correction, for instance, of corneal ulcers,irregularities, scarring, astigmatism, myopia, and hyperopia.

2. Description of the Prior Art

Over the years, methods have been developed to achieve the efficientdelivery of a therapeutic drug to a mammalian body part requiringpharmaceutical treatment. Use of an aqueous liquid which can be appliedat room temperature as a liquid but which forms a semisolid gel whenwarmed to body temperature has been utilized as a vehicle for drugdelivery since such a system combines ease of application with greaterretention at the site requiring treatment than would be the case if theaqueous composition were not converted to a gel as it is warmed tomammalian body temperature. In U.S. Pat. No. 4,188,373, PLURONIC®polyols are used in aqueous compositions to provide thermally gellingaqueous systems. Adjusting the concentration of the polymer provides thedesired sol-gel transition temperature, that is, the lower theconcentration of polymer, the higher the sol-gel transition temperature,after crossing a critical concentration minimum, below which a gel willnot form.

In U.S. Pat. Nos. 4,474,751; '752; '753; and 4,478,822 drug deliverysystems are described which utilize thermosetting gels; the uniquefeature of these systems is that both the gel transition temperatureand/or the rigidity of the gel can be modified by adjustment of the pHand/or the ionic strength, as well as by the concentration of thepolymer.

Other patents disclosing pharmaceutical compositions which rely upon anaqueous gel composition as a vehicle for the application of the drug areU.S. Pat. Nos. 4,883,660; 4,767,619; 4,511,563; and 4,861,760.Thermosetting gel systems are also disclosed for application to injuredmammalian tissues of the thoracic or peritoneal cavities in U.S. Pat.No. 4,911,926.

Ionic polysaccharides have been used in the application of drugs bycontrolled release. such ionic polysaccharides as chitosan or sodiumalginate are disclosed as useful in providing spherical agglomerates ofwater-insoluble drugs in the Journal of Pharmaceutical Sciences volume78, number 11, November 1989, Bodmeier et al. Alginates have also beenused as a depot substance in active immunization, as disclosed in theJournal of Pathology and Bacteriology volume 77, (1959), C. R. Amies.Calcium alginate gel formulations have also found use as a matrixmaterial for the controlled release of herbicides, as disclosed in theJournal of Controlled Release, 3 (1986) pages 229-233, Pfister et al.

In U.S. Pat. No. 3,640,741, a molded plastic mass composed of thereaction product of a hydrophilic colloid and a cross-linking agent suchas a liquid polyol, also containing an organic liquid medium such asglycerin, is disclosed as useful in the controlled release of medicationor other additives. The hydrophilic colloid can be carboxymethylcellulose gum or a natural alginate gum which is cross-linked with apolyol. The cross-linking reaction is accelerated in the presence ofaluminum and calcium salts.

In U.S. Pat. No. 4,895,724, compositions are disclosed for thecontrolled release of pharmacological macromolecular compounds containedin a matrix of chitosan. Chitosan can be cross-linked utilizingaldehydes, epichlorohydrin, benzoquinone, etc.

In U.S. Pat. No. 4,795,642, there are disclosed gelatin-encapsulated,controlled-release compositions for release of pharmaceuticalcompositions, wherein the gelatin encloses a solid matrix formed by thecation-assisted gellation of a liquid filling composition incorporatinga vegetable gum together with a pharmaceutically-active compound. Thevegetable gums are disclosed as polysaccharide gums such as alginateswhich can be gelled utilizing a cationic gelling agent such as analkaline earth metal cation.

While the prior art is silent with respect to aqueous drug deliveryvehicles and isotonicity thereof, osmotic drug delivery systems aredisclosed in U.S. Pat. No. 4,439,196 which utilize a multi-chambercompartment for holding osmotic agents, adjuvants, enzymes, drugs,prodrugs, pesticides, and the like. These materials are enclosed bysemipermeable membranes so as to allow the fluids within the chambers todiffuse into the environment into which the osmotic drug delivery systemis in contact. The drug delivery device can be sized for oral ingestion,implantation, rectal, vaginal, or occular insertion for delivery of adrug or other beneficial substance. Since this drug delivery devicerelies on the permeability of the semipermeable membranes to control therate of delivery of the drug, the drugs or other pharmaceuticalpreparations, by definition, are not isotonic with mammalian blood.

Corneal protective devices are needed in cases in which corneal injuryoccurs and the immobilization of the eye using an eye patch is notresorted to. Molded collagen shields have been developed for this use.These are often not satisfactory because they lack sufficientflexibility to adequately conform to the individual corneal curvature.Wetting a collagen shield will increase conformance of the shield to thecornea but fragmentation can occur upon exceeding the flexibility of thecollagen shield. The clinical uses of collagen shields are disclosed byPoland et al. in Journal of Cataract Refractive Surgery, Volume 14,September 1988, pages 489-491. The author describes the use of collagenshields immersed in tobramycin solution in order to rehydrate thecollagen prior to use. These are described as useful following cataractextraction or in patients having nonsurgical epithelial healingproblems. More rapid healing of epithelial defects after surgeryresulted from the use of the collagen shield. Collagen shields have alsobeen utilized as agents for the delivery of drugs to the cornea asdisclosed in Reidy et al Cornea, in press, 1989 the Raven Press, Ltd.,New York and Shofner et al, Opthalmology Clinics of North America, Vol.2, No. 1, March 1989, pages 15-23.

Refractive surgery has been promoted in the United States and Russiaover the past few years but its acceptance has been limited because ofthe poor predictability of the final optical results which includeresulting glare from incisions that encroach upon the optical zone.Techniques that rely upon the surgical production of corneal incisionshave yielded inconsistent results because these surgical incisions inthe cornea have been found to vary considerably in depth and length.

Laser keratectomy has been shown to be capable of yielding a moreaccurately controlled depth of corneal excision since each individuallaser pulse excises a specific amount (0.2 to 10.0 um) of cornealtissue. Accordingly, the depth of excised tissue is in theory uniformand predictable, provided that the energy distribution is homogeneousacross the laser beam. Since the primary locus of astigmatism is in thecornea, surgical intervention for astigmatism is more important than forthe correction of other refractive errors, especially since spectacle orcontact lens correction is of limited value in compensating for largeastigmatic errors.

The excimer laser was introduced to ophthalmology in 1983 (Trokel, S.,et al., "Excimer surgery of the cornea," Am. J. Ophthalmol. 96: 710-715,1983). The depth of incision with short intense pulses permitted greatprecision to be achieved in tests on freshly enucleated cow eyes. Thephotochemical laser-tissue interaction is not thermal, permitting directbreaks of organic molecular bonds without involving optical breakdown inadjacent tissue. Early experimental results in rabbits revealed problemsof 1) corneal stromal swelling, probably in response to disturbed waterrelationships due to compromise of the epithelial barrier and severingof the lamellae and (2) rearrangement of endothelial cells resultingfrom loss of contact inhibition (Marshall, J., et al., "Anultrastructural study of corneal incisions induced by an excimer laserat 193 nm", Ophthalmology 92: 749-758, 1985). Experiments with freshlyenucleated human eyes indicated that flattening obtained by excimerlaser ablation correlated with results of clinical scalpel radialkeratotormy, but evaluation of the effects on wound healing and possibledamage to adjacent structures was not addressed (Cotliar, A. M., et al.,"Excimer laser radial keratotorny," Ophthalmology 92: 206-208, 1985). Itwas, however, suggested that this laser may become very useful inapplications including penetrating and lamellar keratoplasty,keratomileusis, and epikeratophakia. Control of the area and depth Ofpulses using photolithographed masks resulted in ability to producenarrow cuts (20 um) and at depths depending on pulse number (Puliafito,C. A., et al., "Excimer laser ablation of the cornea and lens", 5Ophthalmology 92: 741-748, 1985). These controlled ablations had onlyvery narrow bands of destruction at the adjacent edges. These studiesled to the quantitation of laser ablation (Kruegar, R. R. and S. L.Trokell "Quantitation of corneal ablation by ultraviolet laser light",Arch. Ophthalmol. 103: 1741-1742, 1985). Excimer far UV radiation can becontrolled to produce minimal adjacent tissue damage providing the angleand depth can be precisely controlled. The remaining problem of effectson healing could then be addressed.

Wound healing was assessed in rabbits following excimer laser surfaceablation (Hanna, K. D., et al., "Corneal stromal wound healing inrabbits after 193 run excimer laser surface ablation", Arch. Ophthalmol.107: 895-901, 1989). Healing appeared to be excellent except when over85% to 90% of the corneal thickness had been cut. Endothelial celldisruption, junction separation and individual cell dropout occurredwith corneal haze development with the deeper cuts. A delivery systemdesigned to deliver predictable depths of cut is, therefore, essential.Similar findings were reported in studies on human blind eyes (Taylor,D. M., et al., "Human excimer laser lamellar Keratectomy", Ophthalmology96: 654-664, 1989). Attention was directed to the challenges of improvedprocedures and equipment, the problems of individual variation, and thecontrol of biologic responses to trauma before excimer laser lamellarkeratectomy could become a clinically useful means of correctingrefractive errors. In living monkey eyes, it was concluded that mild,typical wound healing occurred after excimer laser lamellarkeratomileusis (Fantes, F. E., et &I., `Wound healing after excimerlaser keratomileusis (photorefractive keratectorny) in monkeys", Arch.Ophthalmol. 108: 665-675, 5 1990). All corneas were epithelialized by 7days. By 6 weeks, mild to moderate haze was apparent with clearing by 6to 9 months. The epithelium was thickened at 21 days after ablation, butreturned to normal by 3 months. Subepithelial fibroblasts were threetimes the density of normal keratocytes, but returned to nearly normalnumbers by 9 months. One conclusion reached was that control of thecontour and uniformity of the ablated surface is important forstructural and biological responses of the cornea.

Review of the literature clearly reveals that far UV vaporization(ablation with an excimer laser at 193 nm, for example) is a feasiblemeans to sculpture or reprofile the cornea to correct nearsightedness,farsightedness, astigmatism, corneal scars, corneal densities, etc. Thehealing appears to parallel or to be equal to healing after scalpelintervention, providing the proper guidelines for pulsing and durationare followed. There remains a need to control the contour and uniformityof the ablated surface. Such control will reduce the adverse structuraland biological response of the cornea and insure that a desiredcorrective change results.

The use of a mask, of nearly identical optical density to the cornea,which can be preformed on the corneal surface so as to provide a smoothsurface of exact contour and accurate dimensions would correct many ofthe problems that have prevented the precise control of the laser beenduring keratotorny. This mask would be required to withstand exposure tomoist gases direct tangentally to the corneal surface throughout theduration of exposure to the laser to remove ablated debris. Themodulation of the beam energy distribution of the laser in a controlledfashion should also be provided by such a corneal mask. The use of asmooth ablatable mask having a known contour and having the density ofthe cornea would aid in insuring accurate direction and depth of atangental cut utilizing a laser beam. The ablatable mask of theinvention provides such advantages.

Ionic polysaccharides have been used in the application of drugs bycontrolled release. Such ionic polysaccharides as chitosan or sodiumalginate are disclosed as useful in providing spherical agglomerates ofwater-insoluble drugs in the Journal of Pharmaceutical Sciences, volume78, number 11, November 1989, Bodmeier et al. Alginates have also beenused as a depot substance in active immunization, as disclosed in theJournal of Pathology and Bacteriology, volume 77, (1959), C. R. Amies.Calcium alginate gel formulations have also found use as a matrixmaterial for the controlled release of herbicides, as disclosed in theJournal of Controlled Release, 3 (1986) pages 229-233 , Pfister et al.Alginates have also been used to form hydrogel foam wound dressings, asdisclosed in U.S. Pat. No. 4,948,575.

SUMMARY OF THE INVENTION

Compositions and a process for drug or diagnostic agent delivery bytopical, injection, or body cavity delivery are disclosed. Thepharmaceutical compositions in one embodiment of the invention containpharmacologically active medicaments which are useful in providingtreatments to ophthalmic areas of the mammalian body requiring thecontrolled release application of a medicament or requiring theadministration of a diagnostic agent. In addition, the compositions ofthe invention are useful, with or without the inclusion of a medicament,as injectable compositions for depot drug delivery, as a protectivecorneal shield, as a second skin for application to wounds, as anablatable corneal mask in a laser keratectomy process or, as medicaldevices, for instance, in the separation of organs, injured in surgicalprocedures or otherwise, in order to prevent the formation ofundesirable adhesions as part of the healing process.

The compositions of the invention provide a physiologically acceptablevehicle having a buffered pH and hypoosmotic, hyperosmotic, orisoosmotic characteristics. The pH and osmotic pressure is, preferably,made similar to bodily fluids, such as lacrimal tears. The pH andosmotic pressure of lacrimal tears is about pH 7.4 and 290 mOsm/kg. Inaddition, the pharmaceutical compositions are, optionally, sterilized soas to insure that the pharmaceutical compositions of the invention donot provide a source of infection.

Polyphase systems are also useful and may contain non-aqueous solutes,non-aqueous solvents, and other non-aqueous additives. Homogeneous,polyphase systems can contain such additives as water insoluble highmolecular weight fatty acids and alcohols, fixed oils, volatile oils andwaxes, mono-, di-, and triglycerides, and synthetic, water insolublepolymers without altering the functionality of the system.

The compositions of the invention in a preferred embodiment compriseaqueous mixtures of a film forming, water soluble polymer and an ionicpolysaccharide, optionally containing a latent counter-ion to gel thepolysaccharide upon release of the counter-ion. Alternatively, thecompositions of the invention can comprise a two part aqueous system,one of which contains the ionic polysaccharide and film forming polymerand the other part containing an aqueous solution of a counter-ion.

The counter-ion can be provided in latent form by microencapsulation ina heat sensitive medium, for instance, the walls of the microcapsule canbe made of mono-, di-, or tri-glycerides or other natural or syntheticheat sensitive polymer medium. Alternatively, ion exchange resins can beincorporated in the compositions of the invention so as to release thedesired counter-ion upon contact with an environment opposite in pH tothe pH of the ion exchange resin. The aqueous mixture can be deliveredto the ophthalmic area of the mammalian body requiring treatment as alow viscosity liquid at ambient temperatures. Activation of the latentform of the counter-ion gels the aqueous mixture in situ. The two partsystem can be separately applied to gel the mixture in situ. Because thecompositions of the invention are low viscosity liquids at ambienttemperatures, they easily pass to various ophthalmic areas insuringmaximum contact between exposed tissue and the compositions of theinvention. The gel compositions of the invention can be either peeledaway or allowed to be absorbed over time. The gels are graduallyweakened upon exposure to mammalian body pH conditions.

The useful film forming polymers are, preferably, water soluble polymerssuch as those which have been used in ophthalmic applications. Thehydroxyalkyl cellulosics and methyl celluloses, sodium hyaluronate, andpolyvinyl alcohol are representative polymers which have been founduseful in ophthalmic applications.

The useful ionic polysaccharides are natural polymers such as chitosan,gellan gum or alginates. Aqueous solutions of alginate ionicpolysaccharides form gels upon contact with aqueous solutions ofcounter-ions such as calcium, strontium, aluminum, etc. Aqueoussolutions of chitosan form gels upon contact with a metaltripolyphosphate counter-ion. The discovery forming the basis of thisapplication is that when ionic polysaccharides are present in aqueoussolutions in admixture with film forming polymers and a counter-ion,that such mixtures form useful gels. The osmolality of which can becalculated by assuming that the film forming polymer, if water soluble,does not contribute to the osmolality in the gel state.

DETAILED DESCRIPTION OF THE INVENTION

It has been found that aqueous pharmaceutical vehicles containing a filmforming polymer and an ionic polysaccharide can be gelled and renderedresistant to shear thinning by contacting the mixture with acounter-ion. The gel compositions can be made isotonic or iso-osmoticand adjusted to the pH of mammalian body fluids, such as lacrimal tears.The pH and osmotic pressure of such bodily fluids are 7.4 and 29UmOsm/kg, respectively. It is advantageous to deliver a pharmacologicallyactive medicament to an area of the mammalian body requiringpharmacological treatment under desired pH and osmotic pressureconditions which, for instance, match those of bodily fluids.Optionally, the pharmaceutical compositions of the invention can beprovided in a sterile condition.

A complete listing of useful water soluble, film forming polymers is notpossible. Representative useful polymers are the water soluble alkylcelluloses, i.e., methyl and ethyl cellulose; the hydroxyalkylcelluloses, i.e., hydroxypropylmethyl cellulose and hydroxyethylcellulose; hyaluronic acid and water soluble salts thereof, i.e., sodiumhyaluronate; chondroitin sulfate and water soluble salts thereof i.e.,sodium chondroitin sulfate; polymers of acrylamide, acrylic acid, andpolycyanoacrylates; polymers of methyl methacrylate and 2-hydroxyethylmethacrylate; polydextrose, cyclodextrin; polydextrin; maltodextrin,dextran; polydextrose; gelatin, collagen, natural gums, i.e., xanthan,locust bean, acacia, tragacanth, carrageenan, and agar; derivatives ofpolygalacturonic acid such as pectin; polyvinyl alcohol; polyvinylpyrrolidone; polyethylene glycol; and polyethylene oxide. A preferredfilm forming agent is carboxymethyl ullulose and its sodium salt.

More complete descriptions of some of the preferred water soluble, filmforming polymers are as follows. Cyclodextrin also known as cycloamyloseis a cyclic oligosaccharide. Cyclodextrins are produced by the enzymeconversion of prehydrolized starch to a mixture of alpha, beta, andgamma cyclodextrins and some linear dextrins. The cyclodextrins arecomposed of glucose units linked together by alpha (1-4) glycosidicbonds.

Sodium hyaluronate also known as hyaluronic acid is composed ofrepeating units of sodium glucuronate and N-acetylglucosamine. Sodiumhyaluronate was originally extracted from the comb of the rooster.Hyaluronic acid is a common biological agent present in a number ofsources including the human umbilical cord. Sodium hyaluronate can alsobe manufactured by fermentation of a strain of streptococcuszooepidemicus.

Polydextrose is a randomly bonded condensation polymer of dextrose whichis only partially metabolized by mammals. The polymer can contain aminor amount of bound sorbitol, citric acid, and glucose.

Chondroitin sulfate also known as sodium chondroitin sulfate is amucopolysaccharide found in every part of human tissue, specificallycartilage, bones, tendons, ligaments, and vascular walls. Thispolysaccharide has been extracted and purified from the cartilage ofsharks.

Carrageenan is a linear polysaccharide having repeating galactose unitsand 3,6 anhydrogalactose units, both of which can be sulfated ornonsulfated, joined by alternating 1-3 and beta 1-4 glycosidic linkages.Carrageenan is a hydrocolloid which is heat extracted from severalspecies of red seaweed and irish moss.

Maltodextrins are water soluble glucose polymers which are formed by thereaction of starch with an acid and/or enzymes in the presence of water.

Further details of the composition and derivation of other useful watersoluble, film forming polymers can be found in the HANDBOOK OFPHARMACEUTICAL EXCIPIENTS, published by the American PharmaceuticalAssociation Washington, D.C. copyright 1986, incorporated herein byreference.

The gel forming ionic polysaccharides found useful in the presentinvention are hydrophilic colloidal materials and include the naturalgums such as gellan gum, alginate gums, i.e., the ammonium and alkalimetal salts of alginic acid and mixtures thereof. In addition, chitosan,which is the common name for deacetylated chitin is useful. Chitin is anatural product comprising poly-(N-acetyl-D-glucosamine). Gellan gum isproduced from the fermentation of pseudomonas elodea to yield anextracellular heteropolysaccharide. The alginates and chitosan areavailable as dry powders from Protan, Inc., Commack, N.Y. Gellan gum isavailable from the Kelco Division of Merck & Co., Inc., San Diego,Calif.

Generally, the alginates can be any of the water-soluble alginatesincluding the alkali metal alginates, such as sodium, potassium,lithium, rubidium and cesium salts of alginic acid, as well as theammonium salt, and the soluble alginates of an organic base such asmono-, di-, or tri-ethanolamine alginates, aniline alginates, and thelike. Generally, about 0.2% to about 1% by weight and, preferably, about0.5% to about 3.0% by weight of gellan, alginate or chitosan ionicpolysaccharides, based upon the total weight of the composition, areused to obtain the gel compositions of the invention.

In general, the drug delivery composition of the invention will containabout 0.01% to about 60% by weight of medicament or pharmaceutical,about 1% to about 50% by weight of the water soluble, film formingpolymer, together with the above amounts of ionic polysaccharide and thebalance water. In special situations, these amounts of gel forming ionicpolysaccharide and water soluble, film forming polymer may be varied toincrease or decrease the gel properties.

Many polysaccharides may be used with the present invention to enhancethe physical properties of the gel. For example, carboxymethylcellulosemay reduce the rate of erosion of the polymer when compared to thepolymer without the carboxymethylcellulose. In this regard, thecarboxymethylcellulose competes with the polymer for the association ofthe water molecule, therefore, enhancing the stability of the gel toremain intact when in an aqueous environment.

When polysaccharides are utilized to enhance the physical properties ofthe gel, cross-linking of the polysaccharide is not necessary.

Polysaccharides that have not been crosslinked, and can be used toenhance the physical properties of the gel, include hydroxyalkylcellulose and methylcellulose. More specifically, the usefulpolysaccharides are natural cellulose, hyaluronic acid and water solublesalts thereof, i.e. sodium hyaluronate, chondroitin sulfate and watersoluble salts thereof, i.e. sodium chondroitin sulfate; polydextrose,cyclodextrin, polydextrin, maltodextrin, dextran; polydextrose; gelatin,collagen, natural gums, i.e. xanthan, locust bean, acacia, tragacanth,carrageenan, and agar, and derivatives of polygalacturonic acid such aspectin. A preferred polysaccharide is carboxymethylcellulose.

The drug delivery composition of the invention will contain about a 0.1%to about 25% by weight of the non-crosslinked polysaccharide to enhancethe physical properties of the gel.

If an irreversible gel is required or an elastic gel, that is, one thatretains its shape, cross-linking is required. Cross-linking is thephysical, co-valent or ionic bonding of two or more molecules of thesame polymer.

Any cross linking agent having more than one functional group whereinthe function group is either chemical or ionic may be utilized to crosslink the polysaccharides described above.

As known in the art, cross linking can occur between molecules ofsimilar polymers by physical reaction as long as appropriate functionalgroups are present on the polymers.

Useful counter-ions for gelling the gellan gum or alginate ionicpolysaccharides in combination with the film forming, water solublepolymer compositions of the invention are cationic gelling agents,preferably, comprising a divalent or trivalent cation. Useful divalentcations include the alkaline earth metals, preferably, selected from thegroup consisting of calcium and strontium. Useful trivalent cationsinclude aluminum. The most preferred counter-ions for gelling gellan gumor alginate ionic polysaccharides are contained in ionic compoundsselected from pharmaceutically-acceptable gluconates, flourides,citrates, phosphates, tartrates, sulfates, acetates, borates, chlorides,and the like having alkaline earth metal cations such as calcium andstrontium. Especially preferred counter-ion containing inorganic saltsfor use as ionic polysaccharide gelling agents include such inorganicsalts as the chloride salts, such as strontium chloride, calciumchloride, and mixtures thereof. Generally, a molar ratio of counter-ionto gellan, 5 chitosan or alginate of about 1:1 to about 10:1,preferably, about 2:1 to about 5:1, and, most preferably, about 3:1 toabout 5:1 is used.

While the counter-ion, such as calcium or other counter-ions may beobtained by contact of the compositions of the invention with bodilyfluids, it is preferred that a counter-ion in latent form be used incombination with the gellan gum or alginate ionic polysaccharide andfilm forming, water soluble polymer compositions of the invention.Alternatively, a counter-ion can be combined with the ionicpolysaccharide and water soluble, film forming polymer compositions ofthe invention utilizing a two part system in which the counter-ion istopically or otherwise applied to the compositions of the inventionsubsequent to their topical or other application.

Incorporation of the counter-ion in a latent form together with theionic polysaccharide and film forming, water soluble polymercompositions of the invention may be accomplished by eitherencapsulating an aqueous solution of one of the counter-ion gellingagents, previously described above or by the incorporation of thecounter-ion gelling agent into a matrix which provides for thecontrolled, slow-release of gelatin-encapsulated controlled releasecompositions disclosed in U.S. Pat. No. 4,795,642, incorporated hereinby reference, disclose the preparation of a gelatin shell encapsulatinga controlled release formulation in which the gelatin compositionincludes calcium chloride as the gelling agent. Alternatively, thecounter-ion can be the incorporated as an aqueous solution of a cationicgelling agent encapsulated in a vesical composed, for instance, ofalpha-tocopherol, as disclosed in U.S. Pat. No. 4,861,580, incorporatedherein by reference.

Generally, aqueous compositions comprising chitosan can be gelled withmultivalent anion gelling agents, preferably, comprising a metalpolyphosphate, such as an alkali metal or ammonium polyphosphates,pyrophosphates, or metaphosphates. Representative metaphosphate,pyrophosphate, and polyphosphate gelling agents include sodium andpotassium, polyphosphates, sodium and potassium pyrophosphates, sodiumand potassium metaphosphates, and sodium and ammonium (mono-, di-, tri-)phosphates.

With specific reference to the use of the compositions of the inventionas ophthalmic drug delivery compositions, laser ablatable shields, orcorneal protective compositions, it is noted that, generally, for theavoidance of adverse physiological effects to the eye, it is desirablethat the pH and osmolality of the pharmaceutical vehicle be matched tothe pH and osmolality of the eye. In addition, it is noted that a largepercentage of drugs administered to the eye are lost as a result oflacrimal drainage. This applies especially in situations in which aliquid composition containing a pharmacologically active medicament isapplied to the cornea of the eye. Accordingly, in such cases, only asmall fraction of the pharmaceutical composition administered to the eyeremains in contact with the cornea for a few minutes and an even smallerfraction penetrates into the cornea. To overcome these disadvantages, itis known to use viscous solutions, gels, ointments, or solid eyeimplants containing pharmacologically active medicaments. While progresshas been made in the delivery of drugs by the use of solid implants,many patients find it difficult to tolerate the introduction of theimplants into the conjunctival areas.

To solve this problem, drug delivery vehicles which are liquid at roomtemperature and assume a semi-solid form at human body temperature havebeen proposed, such as those described in U.S. Pat. No. 4,188,373, whichdisclose the use of PLURONIC® polyols. In U.S. Pat. No. 4,861,760 andU.S. Pat. No. 4,474,751, ophthalmic drug delivery systems are disclosedwhich show liquid-gel phase transitions. In the '751 Patent, polymersare disclosed which are tetra substituted derivatives ofethylenediamine, propylenediamine, butylenediamine, pentylenediamine, orhexylenediamine. These are described as block copolymers ofpoly(oxypropylene) and poly(oxyethylene) of various chain lengths. Thesepolymers were utilized as aqueous drug delivery vehicles contain from10% to 50% by weight of polymer based on the weight of the total drugdelivery vehicle. In the '760 Patent, the liquid-gel phase transitioncompositions for ophthalmological use contain polymers which form gelsat concentrations 10-100 fold lower than those used in systems such asthe '751 Patent, involving thermogelation. Accordingly, the drugdelivery vehicles of the '760 Patent are said to be very well toleratedby the eye. The polymers utilized in the drug delivery vehicles of the'760 patent are described as polysaccharides obtained by fermentation ofa microorganism.

The drug delivery vehicles and corneal protective shield compositions ofthe invention are an improvement over those compositions used in priorart methods of ophthalmological drug delivery in that the compositionscan be not only optimized for physiological tolerance in the eye byformulating the vehicles useful as drug delivery compositions so as tohave isoosmotic, hyperosmotic, and hypoosmotic characteristics in thegel state but are made more useful because of increased resistance toshear thinning, as the result of higher gel strength. These advantagesare obtained by the incorporation of an ionic polysaccharide inadmixture with a film forming, water soluble polymer. By matching theosmolality of the drug delivery compositions of the invention, forinstance, to those of the lacrimal fluid of the eye, it is possible toeliminate burning or other discomfort upon application of the drugdelivery vehicles of the invention to the eye. The gel compositionsformed upon contact with a counter ion for the ionic polysaccharideallow retention of the gel at the desired locus for longer intervalsthus increasing the efficiency of action of the delivered drug. Drugs ordiagnostic agents which can be administered by means of the drugdelivery vehicles according to the invention are, for example:

Antibacterial substances such as beta-lactam antibiotics, such ascefoxitin, n-formamidoylthienamycin and other thienamycin derivatives,tetracyclines, chloramphenicol, neomycin, carbenicillin, colistin,penicillin G, polymyxin B, vancomycin, cefazolin, cephaloridine,chibrorifamycin, gramicidin, bacitracin and sulfonamides;

aminoglycoside antibiotics such as gentamycin, kanamycin, amikacin,sisomicin and tobramycin;

nalidixic acid and its analogs such as norfloxacin and the antimicrobialcombination fluoroalanine/pentizidone, nitrofurazones and analogsthereof;

antihistaminics and decongestants such as pyrilamine, chlorpheniramine,tetrahydrazoline, antazoline and analogs thereof; mast-cell inhibitorsof histamine release, such as cromolyn;

anti-inflammatories such as cortisone, hydrocortisone, hydrocortisoneacetate, betamethasone, dexamethasone, dexamethasone sodium phosphate,prednisone, methylprednisolone, medrysone, fluorometholone,prednisolone, prednisolone sodium phosphate, triamcinolone,indainethacin, sulindac, its salts and its corresponding sulfides, andanalogs thereof;

miotics and anticholinergics such as echothiophate, pilocarpine,physostigmine salicylate, diisopropylfluorophosphate, epinephrine,dipivaloylepinephrine, neostigmine echothiopate iodide, demecarimbromide, carbamoyl choline chloride, methacholine, bethanechol, andanalogs thereof;

mydriatics such as atrophine, homatropine, scopolamine,hydroxyamphetamine, ephedrine, cocaine, tropicamide, phenylephrine,cyclopentolate, oxyphenonium, eucatropine, and analogs thereof;

Other drugs can be used in the treatment of conditions and lesions ofthe eyes such as:

antiglaucama drugs, for example, timalol, and especially its maleic saltand R-timolol and a combination of timolol or R-timolol withpilocarpine, as well as many other adrenergic agonists and/orantagonists: epinephrine and an epinephrine complex, or prodrugs such asbitartrate, borate, hydrochloride and dipivefrine derivatives; carbonicanhydrase inhibitors such as acetazolamide, dichlorphenamide,2-(p-hydroxyphenyl)-thiothiophenesulfonamide,6-hydroxy-2-benzothiazolesulfonamide, and6-pivaloyloxy-2-benzothiazolesulfonamide;

antiparasitic compounds and/or anti-protozoal compounds such asivermectin, pyrimethamine, trisulfapidimidine, clindamycin andcorticosteroid preparations;

compounds having antiviral activity such as acyclovir,5-iodo-2'-deoxyuridine (IDU), adenosine arabinoside (Ara-A),trifluorothymidine, interferon, and interferon-inducing agents such aspoly I:C;

antifungal agents such as amphotericin B, nystatin, flucytosine,natamycin and miconazole;

anesthetic agents such as etidocaine cocaine, benoxinate, dibucainehydrochloride, dyclonine hydrochloride, naepaine, phenacainehydrochloride, piperocaine, proparacaine hydrochloride, tetracainehydrochloride, hexylcaine, bupivacaine, lidocaine, mepivacaine andprilocaine;

ophthalmic diagnostic agents, such as:

(a) those used to examine the retina such as sodium fluorescein;

(b) those used to examine the conjunctiva, cornea and lacrimalapparatus, such as fluorescein and rose bengal; and

© those used to examine abnormal pupillary responses such asmethacholine, cocaine, adrenaline, atropine, hydroxyamphetamine andpilocarpine;

ophthalmic agents used as adjuncts in surgery, such asalpha-chymotrypsin and hyaluronidase;

chelating agents such as ethylenediaminetetraacetic acid (EDTA) anddeferoxamine;

immunosuppressants and anti-metabolites such as methotrexate,cyclophosphamide, 6-mercaptopurine and azathioprine and combinations ofthe compounds mentioned above, such as antibiotics/antiinflammatoriescombinations such as the combination of neomycin sulfate anddexamethasone sodium phosphate and combinations concomitantly used fortreating glaucoma, for example, a combination of timolol maleate andaceclidine.

In general the drug delivery composition of the present invention willcontain from about 0.01% to about 60% by weight of the medicament orpharmaceutical, from about 1% to about 50% of the polymer, the aboveamounts of ionic polysaccharide, and the balance water. In specialsituations, however, the amounts may be varied to increase or decreasethe dosage schedule.

If desired, the ophthalmic drug delivery vehicle, laser ablatablecorneal mask, and corneal protective compositions of the invention mayalso contain preservatives, cosolvents, suspending agents, viscosityenhancing agents, ionic-strength and osmolality adjustors and otherexcipients in addition to the medicament and buffering agents. Suitablewater soluble preservatives which may be employed in the inventive drugdelivery vehicle are sodium bisulfite, sodium thiosulfate, is ascorbate,benzalkonilirn chloride, chlorabutanol, thimerosal,phenylmercuricborate, parabens, enzylalcohol phenylethanol and others.These agents may be present, generally, in amounts of about 0.001% toabout 5% by weight and, preferably, in the amount of about 0.01 to about2% by weight.

Suitable water soluble buffering agents are alkali or alkali earthcarbonates, phosphates, bicarbonates, citrates, borates, acetates,succinates and the like, such as sodium phosphate, citrate, borate,acetate, bicarbonate, carbonate and tromethamine (TRIS). These agentsare present in amounts sufficient to maintain the pH of the system at7.4±0.2 and preferably, 7.4. As such the buffering agent can be as muchas 5% on a weight basis of the total composition.

Representative buffering agents or salts useful in maintaining the pH atabout 7.4±0.2 are alkali or alkali earth carbonates, chlorides,sulfates, phosphates, bicarbonates, citrates, borates, acetates andsuccinates. Representative preservatives are sodium bisulfite, sodiumthiosulfate, ascorbate, benzalkonium chloride, chlorobutanol,thimerosal, phenylmercuric borate, parabens, benzylalcohol andphenylethanol.

The corneal mask compositions of the invention are an improvement overthe prior art thermo-reversible gels containing a polyoxyalkylenepolymer as the sole polymer, in that the compositions of the inventionprovide greater gel strength because they are more resistant to shearthinning and are characterized as thermally-irreversible. Theseadvantages are obtained by the incorporation of an ionic polysaccharidein admixture with a water soluble, film forming polymer. They can beoptimized for optimum physiological tolerance in the eye by formulatingthe compositions so as to have a neutral pH and isotoniccharacteristics. These former advantages are obtained by theincorporation of an ionic polysaccharide in admixture with a watersoluble, film forming polymer. By matching the osmolality and pH of thelaser ablatable corneal mask compositions of the invention to those ofthe lacrimal fluid of the eye, it is possible to eliminate burning orother discomfort upon application of the corneal mask of the inventionto the eye. The higher gel strength compositions upon contact with acounter-ion allow retention of the gel as an in situ formed corneal maskfor long intervals.

The preparation of the drug delivery compositions, corneal protectivecompositions, and ablative corneal shield compositions of the inventionis described below. The Examples which follow were prepared, generally,in accordance with the following preparation procedure. A mixture of awater soluble, film forming polymer and ionic polysaccharide is stirredor shaken in admixture with the aqueous buffer solution to bring about amore rapid solution of the polymer. The pharmacologically activemedicaments and various additives such as salts and preservatives cansubsequently be added and dissolved. In some instances thepharmacologically active substance must be suspended since it isinsoluble in water. The pH of 7.4 1 0.2 is obtained by of appropriatebuffering agents.

The following Examples illustrate the various aspects of the inventionbut are not intended to limit its scope. Where not otherwise specifiedthroughout this specification and claims, temperatures are given indegrees centigrade and parts, percentages, and proportions are byweight.

EXAMPLE 1

In this Example there is described a composition of the inventionsuitable for ophthalmic use as a laser ablatable corneal mask orprotective corneal shield. The is composition was characterized asiso-osmotic and neutral I n pH. An aqueous solution was made bydissolving the hydroxypropyl methyl cellulose in aqueous buffer solutiontogether with the sodium alginate. The hydroxypropyl methyl cellulosewas characterized as grade F50LV Premium, obtained from The Dow ChemicalCompany. The sodium alginate, characterized as high viscosity grade HF120 was obtained from Protan, Inc. The proportions of ingredients inpercent by weight are as follows:

    ______________________________________    Hydroxypropyl methyl cellulose                         2.0    Sodium Alginate, high viscosity                         1.0    Glycerin             0.25    Boric acid-sodium borate buffer                         96.75    ______________________________________

The boric acid-sodium borate buffer was prepared as follows: In a twoliter volumetric flask, 24.7 grams of boric acid and 3.8 grams of sodiumborate decahydrate were dissolved in two liters of purified water, Usp.The formulation of this Example had a measured pH of 7.2 and anosmolality of 277 MOSM/Kg. A small amount of the formulation was placedon a glass slide and evenly spread 5 so as to create a thin film. Thefilm was subsequently sprayed with an aqueous solution of calciumchloride having a concentration of 21 to about 5% by weight. The filmwas characterized as strong, transparent, and resembled a thin, softhydrophilic corneal contact lens which would be useful as a protectivecorneal mask or as an ablatable mask useful in laser keratectomy.

The product was further characterized by measuring the averagepenetration in millimeters determined using a Precision Penetrometerwith a 1/4 size (9.38 grams, ASTM D-1043) cone and plunger. Thepenetration of the aqueous solution of polymers prepared above wasgreater than 20 mm. Subsequent to treatment of this solution with a fewdrops of a 2%-5% by weight aqueous solution of calcium chloride, a gelwas formed in which the penetration was reduced to 5 mm.

EXAMPLES 2 AND 3

In these Examples there are described compositions of the invention forophthalmic use as a corneal protective mask or as a laser ablatablecorneal mask. Utilizing the same procedure as described in Example 1, anaqueous composition containing sodium hyaluronate and sodium alginatewas prepared in two separate compositions. Sodium hyaluronate iscommercially available from Meiji Seika Inc. Example 2 was hypoosmotichaving an osmotic pressure of 249 mOSM/Kg and Example 3 was hyperosmotichaving an osmotic pressure of 319 mosm/Kg. Both compositions werecharacterized as neutral in pH. The formulations have the followingproportions by weight:

    ______________________________________                      Example 2                             Example 3    ______________________________________    Sodium hyaluronate  1.0      1.0    Sodium alginate, high viscosity                        1.0      1.0    Glycerin                     0.5    Boric acid-sodium borate buffer                        98.0     97.5    ______________________________________

These compositions were evaluated as described in Example 1 by spreadinga small amount of the formulation on a glass slide and subsequentlyspraying the coated slide with a 5% by weight aqueous solution ofcalcium chloride. Similar strong, transparent, soft films were obtainedwhich would be useful as a protective corneal shield or as a laserablatable corneal mask.

Example 3 was further characterized by measuring the average penetrationin millimeters determined using a Precision Penetrometer with a 1/4 size(9-38 grams, ASTM D-1043) cone and plunger. The penetration of theaqueous solution of polymers prepared above was greater than 20 mm.Subsequent to treatment of this solution with a few drops of a 2%-5% byweight aqueous solution of calcium chloride, a gel was formed in whichthe penetration was reduced to 5.9 mm.

EXAMPLE 4

In this Example there is described a composition of the invention forophthalmic use as a protective corneal shield or a laser ablatablecorneal mask. An aqueous mixture comprising polyvinyl pyrrolidone andsodium alginate, high viscosity was prepared as follows: The percentagesbelow are by weight.

    ______________________________________    Polyvinyl pyrrolidone                         0.8    Sodium alginate, high viscosity                         1.0    Glycerin             0.3    Boric acid-sodium borate buffer                         97.9    ______________________________________

The composition was characterized as neutral in pH having a pH of 7.2.The composition was hypoosmotic having an osmolality of 270 mOsm/Kg.

The product was further characterized by measuring the averagepenetration in millimeters determined using a Precision Penetrometerwith a 1/4 size (9.38 grams, ASTM D-1043) cone and plunger. Thepenetration of the aqueous solution of polymers prepared above wasgreater than 20 mm. Subsequent to treatment of this solution with a fewdrops of a 5% by weight aqueous solution of calcium chloride, a gel wasformed in which the penetration was reduced to 4.1 mm.

EXAMPLE 5

In this Example there is described a composition of the invention forophthalmic use as a laser ablatable mask or as a protective cornealshield. In accordance with the procedure of Example 1, chondroitinsulfate and sodium alginate were prepared as an aqueous solutionutilizing the percentages by weight indicated below.

    ______________________________________    Sodium Chondroitin sulfate                         2.0    Sodium alginate, high viscosity                         1.0    Glycerin             0.3    Boric acid-sodium borate buffer                         96.7    ______________________________________

The aqueous solution was characterized as neutral in pH having a pH of7.0. The aqueous solution was hyperosmotic having a measured osmolalityof 354 mOsm/Kg. The penetration utilizing a Precision Penetrometer witha 1/4 size cone, as described above, was greater than 20 mm prior totreatment with a few drops of a 2%-5% aqueous solution of calciumchloride. Subsequent to treatment with the aqueous calcium chloridesolution, a gel was formed in which the penetration was reduced to 5.1mm.

EXAMPLES 6-10

Ion exchange resin beads sold under the trade name Duolite were treatedso as to incorporate calcium by first treating a 30 gram sample of theion exchange resin with a solution of 0.1 molar hydrochloric acid so asto allow for the exchange of protons for sodium. After three washingswith 0.1 molar hydrochloric acid, the beads were washed with water andthen washed twice with a 2% aqueous solution of calcium chloride. Eachof the washing steps took place over a period of 16 hours (overnight).The beads were thereafter filtered and washed with water utilizingcoarse filter paper and a Buchner glass filter assembly. The beads werethen left overnight in a desiccator to dry. The dried beads of ionexchange resin which were obtained are utilized in the amount of 2 gramsto fill a first compartment (close to the needle of the syringe) of aglass syringe utilized to apply liquids and dry materials. The syringeis sold under the tradename Hypak. Into the second compartment of thesyringe, there is placed successively the solutions of Examples 1-5.Pushing the plunger of the syringe forward results in mixing thesolution of Examples 1-5 with the ion exchange beads. After 5 to 10minutes subsequent to mixing, the mixture is expelled from the syringe.After an additional 15 minutes the expelled material forms (withoutdrying) a strong, transparent gel on the substrate on which it isexpelled.

EXAMPLES 11-15

These examples describe the successive application of an aqueoussolution of Examples 1 and 3-5 to the cornea of a rabbit eye and theconversion of the aqueous liquid to a gel by the application of a 10%calcium chloride solution having a pH of 6.9. The calcium chloridesolution is applied to the concave surface of a contact lens prior tocontacting the surface of the aqueous liquid coating applied upon thecornea of the rabbit eye. After applying the compositions of Examples 1and 3-5 to the cornea of a rabbit while placed under general anesthesia,a liquid coating is formed upon the cornea. Subsequently, a 10% aqueoussolution of calcium chloride is applied to the concave surface of a hardcontact lens and the contact lens is placed over the coating on thecornea of the rabbit eye. The time required for the formation of a gelis less than 5 minutes. Thereafter, the contact lens is removed toexpose a perfectly smooth and optically clear gelled surface of thecomposition of Examples I and 3-5. Excimer laser keratectomy isthereafter performed utilizing an argon fluoride excimer laser (193 nm).

Further details of the excimer laser keratectomey process can be foundin Archives of Ophthalmology, Vol. 106, February, 1988, entitled"Excimer Laser Keratectomy with a Rotating-slit Delivery System", Hannaet al, incorporated herein by reference.

EXAMPLES 16-18

These Examples describe drug compositions of the invention suitable forophthalmic use in comparison with Control Examples in in-vitro tests fordrug release.

EXAMPLE 16 CONTROL Forming no part of this invention

    ______________________________________                        Percentage by weight    ______________________________________    Timolol maleate       0.50    Poloxamer 407         16.00    Sodium phosphate, monobasic, monohydrate                          0.15    Sodium phosphate, dibasic                          0.63    Glycerin              0.75    Sterile water         81.97    ______________________________________

An eye drop or medicated contact lens composition was prepared using asuitable glass container in which the sodium phosphate salts andglycerin were dissolved in sterile water. The polymer was next mixedwith the buffer solution at 65° C. for 1 hour, followed by a further 2-3hours in cold conditions. To a fixed weight of the polymer solution wasadded and dissolved, an accurate amount of timolol maleate (Huhtamaki OYPharmaceuticals, Turku, Finland) to make a 0.5% w/w concentration.

EXAMPLE 17 CONTROL Forming no part of this invention

    ______________________________________                    Percentage by Weight    ______________________________________    Timolol maleate   0.50    Poloxamer         17.00    Sodium alginate, high viscosity                      1.50    Sodium borate, decahydrate                      0.16    Boric acid        1.00    Glycerin          0.30    Sterile water     81.27    ______________________________________

A medicated contact lens was prepared using a suitable glass containerin which the sodium borate, boric acid and glycerin were dissolved insterile water. Sodium alginate was sprinkled in with stirring to form auniform paste. The polymer was next mixed with this mixture at 65° C.for 1 hour, and for a further 2-3 hours under cold conditions. To afixed weight of the polymer-alginate solution, was added and dissolved,an accurate amount of timolol maleate (Huhtamaki OY Pharmaceuticals,Turku, Finland) to make a 0.5% w/w concentration.

EXAMPLE 18

    ______________________________________                    Percentage by weight    ______________________________________    Timolol maleate   0.50    Sodium hyaluronate                      1.00    Sodium alginate, high viscosity                      1.00    Sodium borate, decahydrate                      0.19    Boric acid        1.21    Glycerin          0.50    Sterile water     95.60    ______________________________________

A medicated contact lens was prepared using a suitable glass containerin which the sodium borate, boric acid and glycerin were dissolved tomake a solution in sterile water. Sodium alginate and sodium hyaluronatewere sprinkled into this solution with continuous stirring to form auniform paste. To a fixed weight of the hyaluronate-alginate mixture,there was added and dissolved an amount of timolol maleate (Huhtamaki OYPharmaceuticals, Turku, Finland) to make a 0.5% w/w concentration.

An in-vitro evaluation of the contact lens of Examples 16-18 was carriedout as follows: The medicated contact lens was prepared by accuratelyweighing a big drop of the formulation on a glass microscopic slide(2"×1") . Two drops of a 5% by weight calcium chloride counter-ionsolution was next placed on the formula drop. After 1 minute, the excesscalcium chloride was blotted away from the now formed corneal contactlens.

The glass slide with contact lens in place was next placed at the bottomof the 1 liter dissolution vessel containing 500 ml of purified water,maintained at 37° C. The dissolution experiment was carried out as permethod 2 (paddle) of the United States Pharmacopoeia XXII, page 1579,The United States Pharmacopoeial Convention, Mack Publishing Company,1990. Paddle stirring rate was 50 revolutions per minute.

At regular time intervals, aliquots were removed from the vessels foranalysis by High Pressure Liquid Chromatography. Six vessels were usedfor each formulation (n=6).

    ______________________________________    TIMOLOL MXLEATE DELIVERY FROM CORNEAL LENSES    n = 6    CUMULATIVE % OF TIMOLOL RELEASED (SD)    TIME    Example 16    Example 17                                    Example 18    ______________________________________     0       0.0          0.0           0.0     10 min 100.0         --            --     30 min 100.0         --            --     60 min 100.0         --            --    120 min --             80.3 (12.0)  77.9 (6.2)    240 min --            90.0 (3.8)    93.9 (2.2    360 min --            90.1 (3.1)    94.9 (2.5)    480 min --            95.7 (3.3)    97.5 (2.9)    ______________________________________

It was observed that the drug is released in-vitro, by diffusion and notby the erosion of the lens. Approximately 80% of timolol maleate isreleased in 1 hour and the remaining amount gradually diffuses out in 3to 4 hours. The lenses remained intact 48 hours after the start of theexperiment. On the other hand, when 0.9% sodium chloride was used inplace of purified water as the dissolution medium, the drug was releasedby both erosion and diffusion, within the first hour. The lenses arefirst reduced in size and then dissolved away within 6 hours. Thiserosion is dependent on the replacement of calcium ions (in the lens)with sodium ions (from the dissolution medium). The break up in-vivo isexpected to be slow and gradual and is dependent on the sodiumconcentration in the tear fluid.

In the following examples there are described compositions havingmultiple uses. For instance, they may be used as vehicles for drugdelivery by topical application or by injection or useful as aprotective corneal shield or in a process for excimer laser keratectomyas a laser ablatable corneal mask.

The procedure for preparation and the polymeric materials utilized inthe composition are those described in Example 1. The TRIS-hydrochloridebuffer utilized in this composition was prepared utilizing theingredients and proportions by weight indicated below.

    ______________________________________    TRIS (trcanethamine, USP)                        0.6058    Concentrated hydrochloric acid                        0.4123    Purified water, USP 100    ______________________________________

The composition was found to have a pH of 7.4 and an osmolality inmOsm/kg of 83. The procedure for preparation of this buffer is asfollows: The weighed amount of TRIS was placed in a 2-liter volumetricflask and about 1 liter of purified water was added to the flask. Theconcentrated hydrochloric acid was added and the solution was made up tovolume by adding the remaining water in the formulation.

The calcium based counter-ion solution utilized to gel the inventivedrug delivery compositions of Examples 19-22 was prepared utilizing thefollowing proportions of ingredients in proportions by weight.

    ______________________________________    Calcium chloride, dehydrate                        1.2    Calcium gluconate, anhydrous                        3.0    Purified water, USP 100.0    ______________________________________

The composition had a pH of 6.88 and an osmolality in mOsm/kg of 299.The calcium based counter-ion solution was prepared as follows: TheCalcium gluconate and calcium chloride in the required amount wereplaced in a 200 ml volumetric flask. Approximately 100 ml of water wereadded to partially dissolve the salts. The solution was, thereafter,warmed to 80° C. to facilitate dissolution. The solution was cooled andthe remaining water was added to make up to 200 ml volume.

EXAMPLE 19

A composition containing both sodium alginate and sodium hyaluronate wasprepared for use as a vehicle for drug delivery, a laser ablatablecorneal mask, a protective corneal shield, or a composition for use inpreventing post-surgical adhesions. The proportions by weight are asfollows:

    ______________________________________    Sodium hyaluronate 0.5    Sodium alginate    1.0    Sodium chloride    0.54    TRIS-hydrochloride Buffer                       97.96    ______________________________________

The composition was found to have a pH of 7. 6 and an osmolality of 297mosm/kg prior to treatment with calcium ions by the addition of thepreviously described calcium based counter-ion solution. After treatmentwith calcium ions the osmolality was 302 mosm/kg.

The product was further characterized by measuring the averagepenetration in millimeters as determined using a precision penetrometerwith a 1/4 size (9.38 grams, ASTM D-1043) cone and plunger. Thepenetration in millimeters prior to treatment of the composition ofExample 19 with calcium ions was greater than 20 mm. After treatmentwith calcium ions the penetration was 4.77 mm.

EXAMPLE 20

A composition containing polyvinyl pyrrolidone and sodium alginate wasprepared which is useful for the same applications as that formulationdescribed in Example 19. The proportions in percent by weight of theingredients of the composition are as follows:

    ______________________________________    Polyvinyl pyrrolidone                       0.8    Sodium alginate    1.0    Sodium chloride    0.62    TRIS-hydrochloride buffer                       97.58    ______________________________________

The composition had a pH of 7.59 and an osmolality in mOsm/kg prior totreatment with calcium ions of 320 and after treatment with calcium ionsof 289. The penetration utilizing a precision penetrometer as furtherdescribed in Example 19 was greater than 20 prior to treatment of thecomposition with calcium ions and 6.57 after treatment with calciumions.

EXAMPLE 21

A composition useful for the same uses as stated in Example 19containing a combination of sodium alginate and chondroitin sulfate wasprepared.

The proportions of ingredients in percent by weight are as follows:

    ______________________________________    Sodium chondroitin sulfate                       2.0    Sodium alginate    1.0    Sodium chloride    0.35    TRIS-hydrochloride buffer                       96.65    ______________________________________

The composition had a pH of 7.9 and an osmolality expressed in mOsm/kgof 301 prior to treatment with calcium ions and 272 after treatment withcalcium ions.

The penetration utilizing a precision penetrometer as further describedin Example 19 was found to be greater than 20 mm prior to treatment withcalcium counter-ions and 4.57 upon treatment with calcium ions utilizingthe calcium counter-ion solution prepared above.

EXAMPLE 22

A composition useful for the same uses as stated in Example 19containing a combination of hydroxypropyl methyl cellulose, and sodiumalginate was prepared. The proportions of ingredients and their percentby weight are as follows:

    ______________________________________    Hydroxypropyl methyl cellulose                         2.0    Sodium alginate      1.0    Sodium chloride      0.6    TRIS-hydrochloride buffer                         96.4    ______________________________________

The composition had a pH of 7.59 and an osmolality expressed in mOsm/kgof 326 prior to treatment with calcium ions and 301 after treatment withcalcium ions.

While this invention has been described with reference to certainspecific embodiments, it will be recognized by those skilled in the artthat many variations are possible without departing from the scope andspirit of the invention, and it will be understood that it is intendedto cover all changes and modifications of the invention, disclosedherein for the purposes of illustration, which do not constitutedepartures from the spirit and scope of the invention.

The embodiments of the invention in which an exclusive property orprivilege is claimed are defined as:
 1. An aqueous drug deliverycomposition capable of gelling in situ to produce a hyperosmotic,hypoosmotic or isoosmotic gel having a buffered pH, said compositioncomprising at least one ionic polysaccharide and at least one filmforming agent.
 2. The composition of claim 1 wherein said polysaccharideis capable of cross-linking.
 3. The composition of claim 2 furthercomprising at least one cross-linking agent capable of cross-linking anionic polysaccharide.
 4. The composition of claim 3 wherein saidcross-linking agent is a counter-ion selected from the group consistingof calcium, strontium and aluminum.
 5. The composition of claim 2wherein said polysaccharide is capable of cross-linking upon physicalreaction with other said polysaccharides.
 6. A composition capable ofgelling in situ to produce a hyperosmotic, hypoosmotic or isoosmotic gelhaving a buffered pH, said composition comprising:A) an aqueous vehiclecomprising at least one ionic polysaccharide; and B) an aqueous solutioncomprising a counter-ion capable of gelling said ionic polysaccharide,wherein combining A) and B) results in an aqueous gel vehicle.
 7. Thecomposition of claim 1 wherein said composition further comprises a drugselected from the group consisting of antibacterials, antihistamines,decongestants, antiinflammatories, antiparasitics, miotics,anticholinergies, antivirals, local anesthetics, antifungals,amoebicidals, trichomonocidals, analgesics, mydriatics, antiglaucomadrugs, carbonic anhydrase inhibitors, ophthalmic diagnostic agents,ophthalmic agents used as adjuvants in surgery, chelating agents,antineoplastics, antihypertensives, muscle relaxants and diagnostics. 8.The composition of claim 1 wherein said film forming agent is watersoluble and selected from the group consisting of alkyl methylcelluloses, hydroxyalkyl methyl celluloses, hyaluronic acid, sodiumchondroitin sulfate, polyacrylic acid, polyacrylamide,polycyanolacrylates, alkyl methacrylatepolymers, hydroxyalkylmethacrylate polymers, cyclodextrin, polydextrose, dextran, gelatin,polygalacturonic acid, polyvinyl alcohol, polyvinyl pyrrolidone,polyalkylene glycols and polyethylene oxide.
 9. The composition of claim1 wherein said film forming agent is carboxymethylcellulose.
 10. Thecomposition of claim 1 wherein said ionic polysaccharide is gellan gum,alginate gum or chitosan.
 11. A diagnostic agent vehicle compositioncapable of gelling in situ to produce a hyperosmotic, hypoosmotic orisoosmotic gel having a buffered pH, said composition comprising atleast one ionic polysaccharide and at least one film forming agent. 12.The composition of claim 11 wherein said polysaccharide is capable ofcross-linking.
 13. The composition of claim 12 further comprising atleast one cross-linking agent capable of cross-linking an ionicpolysaccharide.
 14. The composition of claim 13 wherein saidcross-linking agent is a counter-ion selected from the group consistingof calcium, strontium and aluminum.
 15. The composition of claim 12wherein said polysaccharide is capable of cross-linking upon physicalreaction with other said polysaccharides.
 16. The composition of claim11 wherein said film forming agent is water soluble and selected fromthe group consisting of alkyl methyl celluloses, hydroxyalkyl methylcelluloses, hyaluronic acid, sodium chondroitin sulfate, polyacrylicacid, polyacrylamide, polycyanolacrylates, alkyl methacrylatepolymers,hydroxyalkyl methacrylate polymers, cyclodextrin, polydextrose, dextran,gelatin, polygalacturonic acid, polyvinyl alcohol, polyvinylpyrrolidone, polyalkylene glycols and polyethylene oxide.
 17. Thecomposition of claim 11 wherein said film forming agent iscarboxymethylcellulose.
 18. The composition of claim 11 wherein saidionic polysaccharide is gellan gum, alginate gum or chitosan.
 19. Acomposition for the prevention of post-operative adhesions capable ofgelling in situ to produce a hyperosmotic, hypoosmotic or isoosmotic gelhaving a buffered pH, said composition comprising at least one ionicpolysaccharide and at least one film forming agent.
 20. The compositionof claim 19 wherein said polysaccharide is capable of cross-linking. 21.The composition of claim 19 further comprising at least onecross-linking agent capable of cross-linking an ionic polysaccharide.22. The composition of claim 21 wherein said cross-inking agent is acounter-ion selected from the group consisting of calcium, strontium andaluminum.
 23. The composition of claim 20 wherein said polysaccharide iscapable of cross-linking upon physical reaction with other saidpolysaccharides.
 24. The composition of claim 19 wherein said filmforming agent is water soluble and selected from the group consisting ofalkyl methyl celluloses, hydroxyalkyl methyl celluloses, hyaluronicacid, sodium chondroitin sulfate, polyacrylic acid, polyacrylamide,polycyanolacrylates, alkyl methacrylatepolymers, hydroxyalkylmethacrylate polymers, cyclodextrin, polydextrose, dextran, gelatin,polygalacturonic acid, polyvinyl alcohol, polyvinyl pyrrolidone,polyalkylene glycols and polyethylene oxide.
 25. The composition ofclaim 19 wherein said film forming agent is carboxymethylcellulose. 26.The composition of claim 19 wherein said ionic polysaccharide is gellangum, alginate gum or chitosan.
 27. A composition for the treatment oftopical wounds capable of gelling in situ to produce a hyperosmotic,hypoosmotic or isoosmotic gel having a buffered pH, said compositioncomprising at least one ionic polysaccharide and at least one filmforming agent.
 28. The composition of claim 27 wherein saidpolysaccharide is capable of cross-linking.
 29. The composition of claim28 further comprising at least one cross-linking agent capable ofcross-linking an ionic polysaccharide.
 30. The composition of claim 29wherein said cross-linking agent is a counter-ion selected from thegroup consisting of calcium, strontium and aluminum.
 31. The compositionof claim 28 wherein said polysaccharide is capable of cross-linking uponphysical reaction with other said polysaccharides.
 32. The compositionof claim 27 wherein said film forming agent is water soluble andselected from the group consisting of alkyl methyl celluloses,hydroxyalkyl methyl celluloses, hyaluronic acid, sodium chondroitinsulfate, polyacrylic acid, polyacrylamide, polycyanolacrylates, alkylmethacrylatepolymers, hydroxyalkyl methacrylate polymers, cyclodextrin,polydextrose, dextran, gelatin, polygalacturonic acid, polyvinylalcohol, polyvinyl pyrrolidone, polyalkylene glycols and polyethyleneoxide.
 33. The composition of claim 27 wherein said film forming agentis carboxymethylcellulose.
 34. The composition of claim 27 wherein saidionic polysaccharide is gellan gum, alginate gum or chitosan.
 35. Amethod for forming a protective layer over a wound comprising:A)applying a composition comprising at least one ionic polysaccharide andat least one film forming agent to the wound; and B) applying to saidcomposition at least one cross-linking agent capable of cross-linking anionic polysaccharide; wherein application of said agent results in theformation of said protective layer.
 36. The method of claim 35 whereinsaid film forming agent is water soluble and selected from the groupconsisting of alkyl methyl celluloses, hydroxyalkyl methyl celluloses,hyaluronic acid, sodium chondroitin sulfate, polyacrylic acid,polyacrylamide, polycyanolacrylates, alkyl methacrylatepolymers,hydroxyalkyl methacrylate polymers, cyclodextrin, polydextrose, dextran,gelatin, polygalacturonic acid, polyvinyl alcohol, polyvinylpyrrolidone, polyalkylene glycols and polyethylene oxide.
 37. The methodof claim 35 wherein said film forming agent is carboxymethylcellulose.38. The composition of claim 35 wherein said ionic polysaccharide isgellan gum, alginate gum or chitosan.
 39. The method of claim 35 whereinsaid composition further comprises a drug selected from the groupconsisting of antibacterials, antihistamines, decongestants,antiinflammatories, antiparasitics, miotics, anticholinergies,antivirals, local anesthestics, antifungals, amoebicidals,trichomonocidals, analgesics, mydriatics, antiglucoma drugs, carbonicanhydrase inhibitors, ophthalmic diagnostic agents, ophthalmic agentsused as adjuvants in surgery, chelating agents, antineoplastics,antihypertensives, muscle relaxants and diagnostics.